tbuckley/cabot-search huggingface dataset:
EPCT-02. A Phase 1 Study of Mebendazole with Bevacizumab and Irinotecan in High Grade Gliomas
Authors: Julie Krystal, Derek Hanson, Danielle Donnelly, Mark Atlas
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: High grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole (MBZ) is an anti-helminthic benzimidazole. In vitro, MBZ has efficacy in numerous cancer models and is able to cross the blood brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of MBZ in combination with bevacizumab (BVCZ) and irinotecan (CPT-11). OBJECTIVE: To determine the maximally tolerated dose of MBZ when given in combination with BVCZ and CPT-11 in children with high-grade gliomas; to describe the progression-free survival (PFS) and overall survival (OS) for this group. METHODS: Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of MBZ in combination with BVCZ 10mg/kg/dose and CPT-11 150mg/m2/dose. Subjects were eligible upfront after completion of radiation or at the time of progression. MBZ was taken orally twice per day continuously and BVCZ and CPT-11 were given intravenously on days 1 and 15 of 28-day cycles. RESULTS: Between 2015 and 2020, 10 subjects were enrolled at MBZ 50mg/kg/day (n=3), 100mg/kg/day (n=4), and 200mg/kg/day (n=3). One subject assigned to 100mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, 1 subject had anaplastic astrocytoma, and 1 subject had a spinal HGG. All subjects received radiation. There were no dose limiting toxicities. The most frequent G3/G4 adverse events were neutropenia (n=3), and lymphopenia (n= 4). The overall response rate was 33% with 2 subjects achieving a partial response and 1 subject achieving a complete response sustained for 10 months. The PFS and OS from the start of study treatment were 4.7 months and 11.4 months, respectively. CONCLUSION: MBZ was safe and well tolerated when administered with BVCZ and CPT-11 at doses up to 200mg/kg/day. Further studies are needed to determine the efficacy of this treatment.
Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update
Authors: Rahul Seth, Hans Messersmith, Pauline Funchain
Journal: Journal of Clinical Oncology (2022)

ASCO Rapid Recommendations Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options.
Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer.
Authors: Li yuan Guo, Tiantian Han, Didi Guo, Juan Ma, Yaping Zhao, Fanfeng Bu, Siqi Chen, Wanglong Deng, Ran Ding
Journal: Journal of Clinical Oncology (2022)

10584 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer. Pathogenic (harmful) variants（PV) in BRCA1 and BRCA2 are the strongest hereditary risk factors for the development of ovarian cancer. To date, there is little information regarding the frequency of non- BRCA gene PV in Chinese women with OC that undergo genetic cancer risk assessment. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our database. Methods: Peripheral blood of 766 women, diagnosed with ovarian cancer, were taken from the recruited cases with the consent of performing germline genetic testing. Germline mutations including SNV, small INDEL were analyzed by next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 766 OC pts, 460 pts (60%) underwent BRCA1/2 testing only, while 306 pts (40%) consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 16.8% (129/766), while the detection rate for non- BRCA genes was 7.5% (23/306). There was a significant statistical difference in average age that the non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group (62 vs. 57, p=0.018). Wild-type B RCA1/2 OC pathogenic variants (PV), were diagnosed in BLM (n=4, 17.4%), ERCC5 (n=2, 8.7%), MUTYH (n=2, 8.7%), RAD51C (n=2, 8.7%), RAD51D (n=2, 8.7%), ATM (n=1, 4.4%), BRIP1 (n=1, 4.4%), CDH1 (n=1, 4.4%), CHEK2 (n=1, 4.4%), ERCC4 (n=1, 4.4%), LZTR1 (n=1, 4.4%), MSH3 (n=1, 4.4%), PALB2 (n=1, 4.4%), PMS2 (n=1, 4.4%), RAD50 (n=1, 4.4%) and SLX4 (n=1, 4.4%) genes. Of all the 23 non- BRAC gene pathogenicity variations, 57% (13/23) lay in the Homologous Recombination Repair (HRR) pathways. Moreover, a 48-year-old woman with ovarian cancer with two pathogenic variants of the [ BRCA2- MUTYH] genes was detected in the retrospective cohort study. Conclusions: BLM, ERCC5, MUTYH, RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The average age of non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group. Therefore, multi-gene PANEL detection is recommended for ovarian cancer patients, especially for older patients.
Correction: lncRNA-PLACT1 sustains activation of NF-κB pathway through a positive feedback loop with IκBα/E2F1 axis in pancreatic cancer
Authors: Xiaofan Ren, Changhao Chen, Yuming Luo, Mingyang Liu, Yuting Li, Shangyou Zheng, Huilin Ye, Zhiqiang Fu, Min Li, Zhihua Li, Rufu Chen
Journal: Molecular Cancer (2022)
Deuterium Metabolic Imaging Reports on TERT Expression and Early Response to Therapy in Cancer
Authors: Georgios Batsios, Céline Taglang, Meryssa Tran, Nicholas Stevers, Carter Barger, Anne Marie Gillespie, Sabrina M. Ronen, Joseph F. Costello, Pavithra Viswanath
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Telomere maintenance is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT can enable noninvasive assessment of tumor proliferation and response to therapy. Experimental Design: We used RNAi, doxycycline-inducible expression systems, and pharmacologic inhibitors to mechanistically delineate the association between TERT and metabolism in preclinical patient-derived tumor models. Deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, translational metabolic imaging modality, was used for imaging TERT in cells and tumor-bearing mice in vivo. Results: Our results indicate that TERT expression is associated with elevated NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NAD+ biosynthesis, and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which converts NAD+ to NADH. Because NADH is essential for pyruvate flux to lactate, we show that 2H-MRS–based assessment of lactate production from [U-2H]-pyruvate reports on TERT expression in preclinical tumor models in vivo, including at clinical field strength (3T). Importantly, [U-2H]-pyruvate reports on early response to therapy in mice bearing orthotopic patient-derived gliomas at early timepoints before radiographic alterations can be visualized by MRI. Conclusions: Elevated NADH is a metabolic consequence of TERT expression in cancer. Importantly, [U-2H]-pyruvate reports on early response to therapy, prior to anatomic alterations, thereby providing clinicians with a novel tool for assessment of tumor burden and treatment response in cancer.
The prognostic influence of neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) in stage III non-small cell lung cancer (NSCLC) treated with consolidation durvalumab.
Authors: Udit Nindra, Adel Shahnam, Samuel Xavier Stevens, Abhijit Pal, Po Yee Yip, Tamiem Adam, Jenny HJ Lee, Michael J. Boyer, Adnan Nagrial, Steven Chuan-Hao Kao, Victoria Jane Bray
Journal: Journal of Clinical Oncology (2022)

e18773 Background: The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) has been of prognostic interest in lung cancer. Sustained NLR and PLR after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in other solid organ malignancies. This study aims to add to the available evidence by describing the survival outcomes for patients with stage III NSCLC who are treated with consolidation Durvalumab when stratified by baseline or sustained NLR and PLR. Methods: We conducted a retrospective observational cohort study involving 6 sites across Sydney, Australia, including all patients diagnosed with stage III NSCLC treated with chemoradiation (CRT) and at least one cycle of durvalumab between January 2018 to September 2021. Patients had NLR and PLR collected prior to their first treatment of CRT and prior to their first treatment with Durvalumab. We used NLR and PLR values of 3 and 185 respectively to stratify patients into high and low groups. Patients with sustained NLR or PLR were defined as those with values &gt; = 3 or &gt; = 185 at both pre-CRT and pre-Durvalumab time points. Results: 148 patients were included in the study. The median follow-up from the start of Durvalumab was 15.1 months. The median age was 66 years. 61% (n = 90) of patients were male. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached in the pre-CRT NLR low cohort (HR 1.99; 95% CI 1.16 – 3.41; p = 0.01). Median OS was 35.5 months versus 42.0 months in high and low pre-CRT NLR groups respectively (HR 2.62; 95% CI 1.23 – 5.56; p &lt; 0.01). The median PFS was 19.9 months in the pre-CRT high PLR cohort versus and not reached in the pre-CRT low PLR cohort (HR 1.98; 95% CI 1.15 – 3.42; p = 0.02). The median OS was 39.9 months versus 42.0 months in high and low pre-CRT PLR groups respectively (HR 2.29; 95% CI 1.08– 4.88; p = 0.03). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5, 95% CI 1.1 – 2.2, p &lt; 0.01). Similarly median PFS for sustained PLR elevation was 16.6 months versus NR (HR 1.7, 95% CI 1.1 – 2.4, p &lt; 0.01). Conclusions: Pre-CRT NLR and pre-CRT PLR are associated with OS and PFS outcomes in stage III unresectable NSCLC treated with CRT and Durvalumab. Those with sustained NLR or sustained PLR also have worse progression free survival outcomes.
Predictors of early health-related quality of life deterioration in patients receiving radical cystectomy with urinary diversion: Results from a single centre randomized controlled trial
Authors: R. Mastroianni, G. Tuderti, U. Anceschi, A.M. Bove, A. Brassetti, M. Ferriero, L. Misuraca, S. Guaglianone, M. Gallucci, G. Simone
Journal: European Urology (2022)
Enhanced tissue regeneration through immunomodulation of angiogenesis and osteogenesis with a multifaceted nanohybrid modified bioactive scaffold
Authors: Hang Xue, Zhenhe Zhang, Ze Lin, Jin Su, Adriana C. Panayi, Yuan Xiong, Liangcong Hu, Yiqiang Hu, Lang Chen, Chenchen Yan, Xudong Xie, Yusheng Shi, Wu Zhou, Bobin Mi, Guohui Liu
Journal: Bioactive Materials (2022)
Associations between DNA methylation age and chronic health conditions in survivors of childhood leukemia and CNS tumor.
Authors: Maria Monica Gramatges, Wanda LeJeune, Evelyn Hernandez, Philip Lupo, Melissa A. Richard
Journal: Journal of Clinical Oncology (2022)

12088 Background: Survivors of childhood cancer are at risk for treatment related morbidities, including an early onset of chronic health conditions (CHC). Survivors are at risk for epigenetic age acceleration (EAA), i.e. when DNA methylation (DNAm)-predicted age exceeds chronologic age. EAA has been associated with treatment exposures and incidence of cardiometabolic, pulmonary, and neurologic CHC. We characterized the burden of CHCs in survivors of acute lymphoblastic leukemia (ALL) and central nervous system (CNS) tumors, two of the most common childhood cancers, and determined the association between EAA, cancer diagnosis, and burden of CHC. Methods: We included survivors of CNS tumor or ALL diagnosed at Texas Children’s Hospital (TCH) between 1992-2013, who were seen at least once in the TCH Long-Term Survivor Clinic. Demographics, diagnosis, treatment data and date of onset and type of CHC were abstracted from the electronic health record. All CHCs required subspecialty care, were present for at least 1 year, and were classified by system into one of 8 categories. Germline samples were obtained at an average of 10.5 years after diagnosis, and at an average age of 15.9 years of age. Samples were analyzed by Illumina MethylationEPIC BeadChip array on an iScan System in the Baylor College of Medicine (BCM) Laboratory for Translational Genomics. Methylation data were processed using minfi, normalized with noob, and EAA estimated using the Horvath calculator. The relationship between EAA, diagnosis, and CHCs was determined by multivariable linear regression. Results: Endocrine (65%), neuropsychiatric (78%), and sensory/motor (73%) CHCs were common in the CNS tumor group (n = 77). Metabolic (22%) and neuropsychiatric (59%) CHCs were common in the ALL group (n = 268). Survivors of CNS tumor had an earlier time of CHC onset, were more likely to have endocrine and sensory motor outcomes, and less likely to have metabolic outcomes vs. ALL survivors. On average, both survivor groups had EAA: 3.3 years (range: -12.2-15.5 years) for 138 ALL survivors and 4.4 years (range: -0.9-10.9 years) for 38 CNS tumor survivors, but EAA did not differ between diagnoses after adjustment for RT (p = 0.75). For CNS tumor survivors, EAA was 0.8 years greater for each system affected by CHC (beta = 0.8, p = 0.043) after adjustment for RT. For ALL survivors, EAA was not associated with CHCs (p = 0.33), but was associated with RT (p = 0.007). Conclusions: CHCs are prevalent in survivors of childhood ALL and CNS tumors, with patterns that differ by cancer diagnosis. In this cohort of relatively young 5 year + survivors of ALL and CNS tumor, all survivors had similar EAA but demonstrated cancer diagnosis-specific differences in associations between EAA, RT and burden of CHC.
Hybrid peroral endoscopic myotomy for large Zenker’s diverticulum
Authors: Alexandru Lupu, Pierre Lafeuille, Clara Yzet, Nicolas Benech, Jérémie Jacques, Jérôme Rivory, Mathieu Pioche
Journal: Endoscopy (2022)

Zenker's diverticulum is considered a pulsation diverticulum developed in an area of weakness, known as the Killian's triangle. Flexible endoscopic treatment of Zenker's diverticulum was first introduced in 1982 and is now the first line of treatment [1] [2]. It consists of complete section of the abnormal septum by diverticulotomy, using an over-the-scope plastic diverticuloscope that allows stabilization and better exposure. However, this technique does not allow for the accurate estimation of complete myotomy and has a higher risk of perforation, mainly related to the blind introduction of the diverticuloscope [3].
Corrigendum to ‘Fabrication of a bio-instructive scaffold conferred with a favorable microenvironment allowing for superior implant osseointegration and accelerated in situ vascularized bone regeneration via type H vessel formation’ [Bioactive Materials, Volume 9 (March 2022) Page 491–507]
Authors: Yijun He, Wenhao Wang, Shaozhang Lin, Yixi Yang, Lizhi Song, Yihan Jing, Lihao Chen, Zaopeng He, Wei Li, Ao Xiong, Kelvin W.K. Yeung, Qi Zhao, Yuan Jiang, Zijie Li, Guoxian Pei, Zhi-Yong Zhang
Journal: Bioactive Materials (2022)

[This corrects the article DOI: 10.1016/j.bioactmat.2021.07.030.].
Are extended pelvic lymph node dissection-related complications still an issue in contemporary patients treated with robot-assisted radical prostatectomy? A prospective assessment using a standardized collection system
Authors: S.L.A. Scuderi, G. Rosiello, G. Gandaglia, N. Fossati, E. Mazzone, F. Barletta, C.A. Bravi, D. Robesti, R. Leni, L. Toneatto, G. Colandrea, L. D'Ambrosio, E. Zaffuto, F. Dehò, A. Pellegrino, D. Cannoletta, L. Quarta, A. Stabile, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Reduction in local tumor recurrence in a murine R2 resection model comparing locally administered docetaxel-releasing product, OncoPLEX, versus systemic docetaxel.
Authors: Noam Emanuel, Shlomo Nedvetzki, Yosef Rosenfeld, Goldi A. Kozloski, Malka Reichart, Anthony J. Senagore
Journal: Journal of Clinical Oncology (2022)

e22530 Background: Local recurrence (LR) negatively impacts long-term survival and patients’ quality of life in many solid tumor malignancies, despite advances in surgical techniques and neoadjuvant and adjuvant treatments. Systemic treatment-related morbidity and mortality remains an unmet need, especially if only an R2 resection is achievable. OncoPLEX is a biodegradable, extended-release formulation of docetaxel that is applied in the form of a paste to the resection bed at surgery. We evaluated OncoPLEX efficacy in preventing local recurrence in an R2 tumor resection model generated with cell lines that exhibit high or low docetaxel sensitivity. Methods: Cell lines sensitivity to free docetaxel and OncoPLEX-released docetaxel were determined in a cytotoxic assay. CT26 (murine colorectal carcinoma--resistant) and U-87 (human primary glioblastoma—sensitive) were tested. A murine subcutaneous (SC) tumor resection model using a predetermined tumor size (400-600 mm 3 ) and a standardized R2 resection (̃90%) was developed. OncoPLEX was applied once on the tumor bed post-resection, docetaxel was IV injected every 4 days (6 times total), and animals were followed for tumor regrowth. The overall docetaxel dose in OncoPLEX (0.78 mg docetaxel) is lower than the maximal tolerated dose and non-lethal reported dose (TAXOTERE [10 mg/kg IV]; prescribing information). Results: The IC 50 concentrations of free docetaxel in CT26 and U-87 cell lines indicated resistance and sensitivity to docetaxel respectively (112.6 nM vs 4.2 nM). The cytotoxic potency of OncoPLEX-released docetaxel exhibited a similar relationship with greater potency (IC 50 values in CT26 56.7 vs. 1.2 nM in U-87). At the completion of the CT26 SC study (37 days), there were more tumor-free animals in the OncoPLEX group (6/8, 75%) compared with the control IV docetaxel treated (3/8, 38%) or the untreated control (0/8, 0%). A similar trend was observed in the U-87 study; OncoPLEX (4/10, 40%), Control intraperitoneal-injected taxel (2/10, 20%), and untreated control (0/10, 0%). In both studies, the average tumor volume was significantly smaller with either OncoPLEX or systemic treatment compared with untreated controls (CT26: 375 mm 3 , 485 mm 3 and 1500 mm 3 (p&lt;0.05); U-87, 403 mm 3 , 780 mm 3 and 2059 mm 3 ; p&lt;0.001). There was no effect on behavior or weight in the OncoPLEX treated animals. Conclusions: Locally administered OncoPLEX in this R2 resection model reduced local tumor recurrence and systemic adverse outcomes. OncoPLEX offers a potentially enhanced local adjuvant chemotherapy option with reduced side effects for solid tumors, independent of the tumor sensitivity or resistance to docetaxel.
Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts
Authors: Pamela González-Dávila, Markus Schwalbe, Arpit Danewalia, René Wardenaar, Boushra Dalile, Kristin Verbeke, Sushil K Mahata, Sahar El Aidy
Journal: Gut Microbes (2022)

The gut microbiota is in continuous interaction with the intestinal mucosa via metabolic, neuro-immunological, and neuroendocrine pathways. Disruption in levels of antimicrobial peptides produced by the enteroendocrine cells, such as catestatin, has been associated with changes in the gut microbiota and imbalance in intestinal homeostasis. However, whether the changes in the gut microbiota have a causational role in intestinal dyshomeostasis has remained elusive. To this end, we performed reciprocal fecal microbial transplantation in wild-type mice and mice with a knockout in the catestatin coding region of the chromogranin-A gene (CST-KO mice). Combined microbiota phylogenetic profiling, RNA sequencing, and transmission electron microscopy were employed. Fecal microbiota transplantation from mice deficient in catestatin (CST-KO) to microbiota-depleted wild-type mice induced transcriptional and physiological features characteristic of a distorted colon in the recipient animals, including impairment in tight junctions, as well as an increased collagen area fraction indicating colonic fibrosis. In contrast, fecal microbiota transplantation from wild-type mice to microbiota-depleted CST-KO mice reduced collagen fibrotic area, restored disrupted tight junction morphology, and altered fatty acid metabolism in recipient CST-KO mice. This study provides a comprehensive overview of the murine metabolic- and immune-related cellular pathways and processes that are co-mediated by the fecal microbiota transplantation and supports a prominent role for the gut microbiota in the colonic distortion associated with the lack of catestatin in mice. Overall, the data show that the gut microbiota may play a causal role in the development of features of intestinal inflammation and metabolic disorders, known to be associated with altered levels of catestatin and may, thus, provide a tractable target in the treatment and prevention of these disorders.
Trends and Disparities in Access to Buprenorphine Treatment Following an Opioid-Related Emergency Department Visit Among an Insured Cohort, 2014-2020
Authors: Maria A. Stevens, Jennifer Tsai, Samuel T. Savitz, Bidisha Nath, Edward R. Melnick, Gail D’Onofrio, Molly Moore Jeffery
Journal: JAMA Network Open (2022)

This cross-sectional study examines trends in access to buprenorphine treatment following an opioid-related emergency department (ED) visit among adults with commercial or Medicare Advantage health insurance between 2014 and 2020.